The administration of high doses of 3,4-methylenedioxymethamphetamine (MDMA) reduces the concentration of serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), for 4-6 weeks in rodents and primates. In spite of numerous reports on the neurotoxic effects of MDMA, the mechanism(s) responsible for the depleting effects of MDMA have not been elucidated. It has been hypothesized that dopamine (DA) may play a role in the 5-HT depleting effect of MDMA. That is, excessive DA released into the synapse may be taken up by 5-HT axon terminals and converted to a toxic metabolite(s). The proposed studies will measure the acute release of DA, 5-HT and their metabolites using in vivo microdialysis following the systemic or local administration of MDMA. The measurement of DA, 5-HT and their metabolites using in vivo microdialysis following the systemic or local administration of MDMA. The measurement of DA, 5-HT and their metabolites will be accomplished by inserting a dialysis probe into either the striatum or nucleus accumbens and collecting perfusates at set time intervals (30 min over a 4 hr time period). The perfusate will be injected into an HPLC and the concentrations of the monoamines will be determined. Since the striatum is sensitive to the long-term 5-HT depleting effects of MDMA, whereas the nucleus accumbens is relatively resistant to MDMA- induced 5-HT depletion, the proposed studies will focus on these brain areas. The initial studies will determine the relative ability of MDMA to release 5-HT and DA in the striatum as compared to the nucleus accumbens following systemic or local administration. The effect of MDMA on DA and 5-HT release will also be tested in rats pretreated with either alpha-methylparatyrosine or parachlorophenylalanine, inhibitors of tyrosine and tryptophan hydroxylase, respectively. These studies will examine the effect of DA depletion on 5-HT release and 5-HT depletion on DA release in the striatum and nucleus accumbens following MDMA administration. Finally, the effect of the 5-HT2 antagonist, ketanserin, on MDMA-induced DA release in the striatum will be examined, since pretreatment with ketanserin blocks MDMA-induced long-term 5-HT depletion in the striatum. The long-term objectives of these studies are to: 1) provide the first direct evidence that MDMA administration increases DA and 5-HT release in the striatum and nucleus accumbens; 2) determine the effect of MDMA on neurotransmitter release following depletion of DA or 5-HT and 3) determine the site of action where MDMA stimulates the release of DA and 5-HT. These data may be applicable to the mechanism of action of structurally related phenethylamines.